556MO - A phase II clinical trial of sintilimab plus chidamide combined with or without bevacizumab in patients with MSS/pMMR metastatic colorectal cancer

Background

Immune checkpoint inhibitors(ICI) have shown significant clinical benefit for MSI-H/dMMR metastatic colorectal cancer (mCRC) patients. However, the majority of MSS/pMMR mCRC patients show no response to immunotherapy and better combinations are currently lacking. Based on our preclinical research, we designed a study to explore whether an ICI sintilimab combined with an HDAC inhibitor chidamide, with or without bevacizumab would show efficacy in MSS/pMMR mCRC patients.

Methods

This open-label, multicenter trial (NCT04724239) recruited patients with MSS/pMMR mCRC that had failed or were intolerant to at least two lines of systemic therapies. The patients were randomly assigned to two arms, sintilimab plus chidamide (doublet) group, and sintilimab plus chidamide combined with bevacizumab (triplet) group. Patients in the doublet group received sintilimab 200 mg IV q3w plus chidamide 30 mg PO biw. Patients in the triplet group received sintilimab 200 mg IV q3w plus chidamide 30 mg PO biw and bevacizumab 7.5 mg/kg IV q3w. The primary endpoint was progression-free survival rate achieved at 18 weeks (18wPFS). The secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety.

Results

Between March 2021 and April 2022, 23 and 25 patients were randomly allocated to the doublets group and triplets group. 18wPFS was 17.4% in the doublets group and 66.7% in the triplets group (P = 0.0012). ORR was 13.0% and 44.0%, and DCR was 39.1% and 72.0% in the doublets and triplets group. The median PFS was 1.5 months with doublets and 7.3 months with triplets (P = 0.008). The median OS for the triplet arm had not been reached, while the median overall survival for the doublet arm was 18.9 months (P = 0.41). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.9%), thrombocytopenia (43.5%), and animea (39.1%) with doublets and thrombocytopenia (72.0%), proteinuria (72.0%), and neutropenia (60.0%) with triplets. Grade 3 and above TEAEs occurred in 7 (30.4%) patients in the doublet arm and 13 (42.0%) patients in the triplet arm.

Conclusions

Sintilimab combined with chidamide and bevacizumab had promising efficacy and tolerable toxicity in MSS mCRC patients.

Clinical trial identification

NCT04724239.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Innovent Biologics, Inc. and Shenzhen Chipscreen Biosciences Co., Ltd

Disclosure

All authors have declared no conflicts of interest.